&NA;In vitro studies of the canine basilar artery have demonstrated that calmodulin antagonism can effectively inhibit cerebral arterial smooth muscle contractility. The prophylactic and therapeutic effectiveness of a potent calmodulin antagonist, the phenothiazine compound trifluoperazine (TFP), was investigated in vivo over a wide range of doses in the well‐documented “double‐subarachnoid hemorrhage” canine model of cerebral vasospasm. The compound is perhaps more well‐known under its trade name, Stelazine, as a classic antipsychotic drug. The drug demonstrated no therapeutic relief of preexisting chronic cerebral vasospasm at any time during 2 days of systemic administration at any practical dose. At doses far in excess of the normally accepted therapeutic range in humans, a prophylactic regimen reduced the severity of chronic cerebral vasospasm after subarachnoid hemorrhage by approximately 35% compared to untreated dogs. (Neurosurgery25:917‐922, 1989)